The complex genetic architecture of Alzheimer's disease: novel insights and future directions

Abstract

Background: Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder and the most common form of dementia. AD is highly heritable, with heritability estimates of ∼70% from twin studies. Progressively larger genome-wide association studies (GWAS) have continued to expand our knowledge of AD/dementia genetic architecture. Until recently these efforts had identified 39 disease susceptibility loci in European ancestry populations.

Recent developments: Two new AD/dementia GWAS have dramatically expanded the sample sizes and the number of disease susceptibility loci. The first increased total sample size to 1,126,563-with an effective sample size of 332,376-by predominantly including new biobank and population-based dementia datasets. The second, expands on an earlier GWAS from the International Genomics of Alzheimer's Project (IGAP) by increasing the number of clinically-defined AD cases/controls in addition to incorporating biobank dementia datasets, resulting in a total sample size to 788,989 and an effective sample size of 382,472. Collectively both GWAS identified 90 independent variants across 75 AD/dementia susceptibility loci, including 42 novel loci. Pathway analyses indicate the susceptibility loci are enriched for genes involved in amyloid plaque and neurofibrillary tangle formation, cholesterol metabolism, endocytosis/phagocytosis, and the innate immune system. Gene prioritization efforts for the novel loci identified 62 candidate causal genes. Many of the candidate genes from known and newly discovered loci play key roles in macrophages and highlight phagocytic clearance of cholesterol-rich brain tissue debris by microglia (efferocytosis) as a core pathogenetic hub and putative therapeutic target for AD. WHERE NEXT?: While GWAS in European ancestry populations have substantially enhanced our understanding of AD genetic architecture, heritability estimates from population based GWAS cohorts are markedly smaller than those from twin studies. While this missing heritability is likely due to a combination of factors, it highlights that our understanding of AD genetic architecture and genetic risk mechanisms remains incomplete. These knowledge gaps result from several underexplored areas in AD research. First, rare variants remain understudied due to methodological issues in identifying them and the cost of generating sufficiently powered whole exome/genome sequencing datasets. Second, sample sizes of non-European ancestry populations in AD GWAS remain small. Third, GWAS of AD neuroimaging and cerebrospinal fluid endophenotypes remains limited due to low compliance and high costs associated with measuring amyloid-β and tau levels and other disease-relevant biomarkers. Studies generating sequencing data, including diverse populations, and incorporating blood-based AD biomarkers are set to substantially improve our knowledge of AD genetic architecture.

Keywords: Alzheimer's disease; Genome-wide association study; Review.

Fig. 1

Genetic architecture of AD/dementia highlighting ADAD mutations and 81 genome-wide significant loci. Genetic variants associated with disease are often conceptualized along two dimensions–variant effect size and population minor allele frequency. Highly penetrant mutations in APP, PSEN1, PSEN2 that segregate with autosomal dominant AD are extremely rare and have large effect sizes. Variants discovered by genome-wide associations are mostly common to low-frequency with small effect sizes. To date, AD/dementia GWAS have identified 101 independent AD-associated single nucleotide polymorphisms across 81 genome-wide significant (p < 5e-8) loci. The shaded area illustrates 80% power to detect genome-wide significant association for variants at a given effect size and population frequency between an effective sample size of 382,472 from Bellenguez et al. (2022) (top) and 1 million (bottom), assuming 0.18 AD prevalence. Odds ratios are reported on the absolute scale, with triangles indicating directionality for APOE genotypes and rare variants with moderate-high SnpEff impact annotations. Effect sizes for APOE genotypes and APP Ala673Thr were obtained from Reiman et al. and Jonsson et al., respectively. Labeled loci indicate candidate causal genes prioritized by Bellenguez et al. (2022). Variant MAFs and APOE genotype frequencies were obtained from the gnomAD global population (GRCh37 v2.1.1).

Fig. 2

AD/dementia genome-wide significant loci. AD/dementia GWAS have found an increasing number of associated loci as effective sample size has increased, collectively identifying 101 independent variants across 81 loci. Full points represent loci that reach genome-wide significance in a given study, and red points represent loci harboring multiple independent associated variants. Loci are labeled based on candidate causal genes prioritized by Bellenguez et al. (2022) and Wightman et al. (2022).

Fig. 3

Prioritized AD risk genes with roles in microglial efferocytosis. Both common and rare genetic variants associated with Alzheimer's disease point to several genes with important roles in one of the most fundamental functions of all macrophages, the phagocytic clearance of dead cells and other cellular “waste” (a process termed “efferocytosis”). Efferocytosis is essential for the maintenance of tissue homeostasis and immune tolerance, and for the resolution of inflammation. Accordingly, defective efferocytosis underlies several autoimmune and chronic inflammatory diseases, and it is thought to contribute to the pathogenesis of several other disorders. Efferocytosis is a multi-step process that involves: 1) finding dead cells by virtue of receptors located on the surface of macrophages that recognize “eat-me” (e.g., phosphatidylserine, PtdSer) as well as “don't eat-me” (e.g., sialylated glycoproteins/lipids) signals presented on the surface of dead and live cells, respectively; 2) internalization of dead cells by phagocytic uptake into phagosomes (Engulfment), 3) digestion of dead cells by the fusion of phagosomes with lysosomes (“Digest me”. Endolysosomal processing); 4) functional (e.g., transcriptional, metabolic, and inflammatory) adaptation of macrophages to molecules derived from the phagolysosomal decomposition of cell corpses, e.g., cholesterol, which activates LXR:RXR nuclear receptors to regulate the expression of genes (e.g., AD-associated genes ABCA1 and APOE) involved in the removal of cholesterol from macrophages (“Poop me”. Adaptation, storage, elimination). With the exception of genes colored in gray, all genes shown in this figure to be involved in the various steps of efferocytosis have also been implicated in the etiology of AD by GWAS and post-GWAS studies. Genes in green font were prioritized or nominated through integration analyses.^,,, , Thus human genetics evidence strongly suggests that efferocytosis may act as a pathogenetic hub for Alzheimer's disease in macrophages, including microglia in the brain. Created with BioRender.com.